Abstract
Smoking and HPV infection are known causes for the vast majority of head and neck squamous cell carcinomas (HNSCC) due to their likelihood of causing gene dysregulation and genomic alterations. Enhancer RNAs (eRNAs) are non-coding RNAs that are known to increase nearby and target gene expression, and activity that has been suggested to be affected by genetic and epigenetic alterations. Here we sought to identify the effects of smoking and HPV status on eRNA expression in HNSCC tumors. We focused on four patient cohorts including smoking/HPV+, smoking/HPV−, non-smoking/HPV+, and non-smoking/HPV− patients. We used TCGA RNA-seq data from cancer tumors and adjacent normal tissue, extracted eRNA read counts, and correlated these to survival, clinical variables, immune infiltration, cancer pathways, and genomic alterations. We found a large number of differentially expressed eRNA in each patient cohort. We also found several dysregulated eRNA correlated to patient survival, clinical variables, immune pathways, and genomic alterations. Additionally, we were able to find dysregulated eRNA nearby seven key HNSCC-related oncogenes. For example, we found eRNA chr14:103272042–103272430 (eRNA-24036), which is located close to the TRAF3 gene to be differentially expressed and correlated with the pathologic N stage and immune cell populations. Using a separate validation dataset, we performed differential expression and immune infiltration analysis to validate our results from the TCGA data. Our findings may explain the association between eRNA expression, enhancer activity, and nearby gene dysregulation.
Highlights
Head and Neck Cancer is a cancer that develops in the oral or nasopharyngeal cavity, and most often in the squamous cells lining the mucosa of the head and neck area
For head and neck squamous cell carcinoma (HNSCC) primary tumor (520 samples) and adjacent solid tissue normal samples (44 samples). Enhancer RNAs (eRNAs) transcripts were downloaded from SlideBase [22], and read counts were extracted from The Cancer Genome Atlas (TCGA) data using Bedtools
Further analyses were conducted on the patient cohorts to elucidate the role of smoking and Human papillomavirus (HPV) status on eRNA
Summary
Head and Neck Cancer is a cancer that develops in the oral or nasopharyngeal cavity, and most often in the squamous cells lining the mucosa of the head and neck area. While advances in research and treatments have led to high survival rates in other cancers such as breast and prostate [4], the 5-year relative survival rate of HNSCC, between 2011–2017, remained unchanged at a modest 67% [5]. ERNAs were discovered relatively recently, in 2010 [7]. In any given cell type, the enhancers that are not transcribed will outnumber those that are. As such, their functions and mechanisms have yet to be elucidated. Research has shown that eRNAs tend to remain in the nucleus after being transcribed and are degraded relatively quickly [8]. Transcription of eRNA is an indication that an enhancer is active [9]
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